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Systematic (IUPAC) name
5'-Inosinic acid, homopolymer, complex with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1)
Clinical data
Trade names Ampligen
Routes of
CAS Registry Number 38640-92-5
ATC code None
ChemSpider 34908 YesY
UNII 94325AJ25N
NIAID ChemDB 000136
Synonyms PolyI:PolyC12U
Chemical data
 YesY (what is this?)  (verify)

Rintatolimod (tradename Ampligen, also known as poly I:poly C12U), is a immunomodulatory double stranded RNA drug synthesized in the 1970s and manufactured by Hemispherx Biopharma of Philadelphia, Pennsylvania.[1] Rintatolimod has been proposed and tested as a treatment for illnesses including chronic fatigue syndrome (CFS), acquired immunodeficiency syndrome (AIDS), and as a synergist with existing antivirals for Avian Flu.[2][3] Although Ampligen was cleared for use in Canada in 1997,[4] and obtained orphan drug status for treatment of CFS in the Europen Union in 2000,[5] it is so far without FDA approval and therefore classed as experimental in the United States.

In 2004 Hemispherx reported it had completed a Phase III double-blind clinical trial for CFS.[6] In 2007 it filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) to market and sell rintatolimod for the treatment of CFS,[7] but this was rejected in December 2009 because the FDA concluded that the two RCTs "did not provide credible evidence of efficacy"[8][9] and "because of clinical, statistical, clinical pharmacology, nonclinical, product quality, and facilities inspection deficiencies."[10] The FDA requested Hemispherx conduct at least one additional controlled trial to demonstrate efficacy in treating CFS. In August 2012 Hemispherx submitted further analyses of the original clinical trial data, although did not submit additional trials for review. Four months later a committee of the FDA voted 8-5 against approval for Ampligen, again citing insufficient data.[10]


Rintatolimod development builds on a 1960s synthesis by Merck & Co., a double-stranded RNA compound of inosinic and cytidylic acid residues (poly I:poly C or poly I:C). Poly I:C inhibited tumor growth by inducing interferon production but was too toxic to use. In the mid-1970s, William A. Carter, a post-doctoral researcher at Johns Hopkins University, modified the dsRNA molecule by adding uridylic acid molecules at specific interval along the RNA chain. The new compound, called Ampligen (for AMPLIfied GENetic activity) stimulated interferon production like poly I:C, but was far kinder to the rest of the body.[11]

Dr. Carter founded a company based upon the compound and licensed it from Johns Hopkins. By the late 1980s, Carter and his company, HEM Research, Inc., were pursuing human therapeutic uses for rintatolimod, as well as non-therapeutic uses, such as diagnostic testing for HIV and protecting plants from pathogens.[12]

Ampligen was tested in clinical trials in United States of America beginning in 1988, after DuPont invested $30 million in Hemispherx. Initial success in a small trial for AIDS treatment was followed by difficulties in persuading the FDA to permit large scale trials. By 1991, it was thought that the chance of approval for a large trial being conducted in the USA had gone. Hemispherx then began to move clinical trials to Canada and Belgium.[13]

In Belgium, rintatolimod has been available for use since the drug's trial beginning in May 1996. It has also been available under Canada's Emergency Drug Release Program for both chronic fatigue syndrome (CFS) and HIV treatment since 1996, with marketing rights controlled by Biovail Corporation International.[14] An agreement between the Spanish company Esteve and Hemispherx in 2002 gave Esteve the rights to perform clinical trials at their own cost in Spain, Portugal, and Andorra.[15] Bioclones (PTY) Ltd, a UK based company, was granted the exclusive marketing rights to rintatolimod in the United Kingdom, Ireland, and several countries in the Southern Hemisphere.[16] The marketing agreement with Bioclones was terminated in 2005.[17] Over its developmental history rintatolimod has received various designations including “orphan drug product” and “emergency compassionate cost recovery sales authorization,” both from the FDA, and "promising" clinical outcome recognition based on the evaluation of certain summary clinical reports (AHRQ, Agency Health Research Quality).[18]

According to the US National Academy of Sciences Institute of Medicine, "Chronic Fatigue Syndrome is a disease characterized by profound fatigue, cognitive dysfunction, sleep abnormalities, autonomic manifestations, pain, and other symptoms that are made worse by exertion of any sort. CFS can severely impair patients’ ability to conduct their normal lives."[19] In October 2007 Hemispherx BioPharma submitted their first New Drug Application (NDA) to the FDA for Ampligen to treat CFS. In December 2007 the agency deemed the application incomplete, citing deficiencies including lack of dose ranging, statistical analysis plans inconsistent with protocols, database discrepancies, and lack of clinical pharmacology and carcinogenicity data.[20] In early 2009 Hemispherx again submitted Ampligen for FDA approval for CFS treatment. The FDA scheduled their decision for May 25th of that year and twice postponed.[21][22] The company received a Complete Response Letter from the agency on Ampligen's NDA in December 2009 requesting further data.[23]

In 2007, and again during the 2009 swine flu outbreak, William Carter said that rintatolimod could also be used as an H1N1 flu vaccine booster, citing in vitro studies with Ampligen and neuraminidase inhibitors oseltamivir and zanamivir (brand names Tamiflu and Relenza).[24]

Hemispherx Biopharma continues to work with the FDA on Ampligen approval for CFS treatment. On December 20, 2012 an FDA Advisory Committee voted in favor of Ampligen's safety for commercial use (vote 8 to 5), but not in favor of its efficacy (4 to 9).[25] The Complete Response Letter asked for more study data prior to Ampligen approval.[26] Recently, on January 12, 2015, the company released new in vitro study findings showing that low natural killer cell function associates with greater CFS disease symptom severity, and that Ampligen treatment increases average NK cell activity over 100%. The new study report, “Low Natural Killer (NK) Activity Observed Across the Chronic Fatigue Syndrome (CFS) Disease Spectrum,” has been submitted as a scientific paper for peer-review and publication. In addition to the new study findings the paper summarizes 6 supportive publications of results with more than 150 CFS patients correlating increased debility of CFS and low NK cell activity.[27] Clinical testing is currently underway to determine whether NK cell activity augmentation by Ampligen in vivo associates with lessened CFS disease severity and increased physical endurance and performance measures.[28]

Hypothesized mechanism of action[edit]

A primary way rintatolimod, tradename Ampligen, acts is by protecting and stimulating the innate immune system, also called the nonspecific immune system and the first line of defense.[29] According to a study published in the Journal of Immunology[30] and reflected in a press release by Hemispherx,[7] Ampligen protects and stimulates the innate immune system by binding to Toll-like receptors 3 (TRL-3), and activating the TLR-3 receptors for broad-spectrum immune response. TLR-3 receptors are located on cell surfaces. They are part of a family of “pattern recognition” receptors that detect pathogens immediately, even those the body has not yet encountered, long before adaptive immunity can intervene against foreign invaders. These receptors are critical to the first line of immunological defense against a broad range of pathogens, including otherwise lethal viruses and various forms of cancer. When, for example, double-stranded RNA molecules from an RNA viral infection bind to TLR-3 receptors the virus in this way inactivates the innate immune system, rendering it unable to signal the rest of the body's defenses. When Ampligen binds to TRL-3 receptors the virus cannot do so and the body is able to marshal its defenses and launch an assault on the virus.

Most antivirals target only one pathogen and become less effective or non effective with viral mutation. So Ampligen, with its broad-spectrum pathogen target capabilities and apparent ability to overcome mutational drift, can sound too good to be true.[31] Only recently with the advent of sophisticated genome detection technology are Ampligen's mechanisms of action finally becoming unlocked.[32]

The mechanism of Ampligen in relation to CFS is not certain but is thought to include the RNase L enzyme.[33] Ampligen is a dsRNA, and when TLR-3 senses a dsRNA it is thought to relay a message to cells to produce interferons (IFNs).[34] IFNs are a group of signaling molecules released by cells in response to the presence of pathogen viruses or bacteria. These signaling molecules activate (among other things) the protective defenses of the immune system that eradicate pathogens. One such defense mechanism thought to be activated by Ampligen is the production of enzyme RNase L. This enzyme degrades pathogenic RNA both viral and cellular. Degradation of RNA prevents viral and cell replication, and destruction of all RNA within a virus or cell is the last stand before apoptosis or death. Accumulation of an inactive form of RNase L may be associated with CFS.[35]

Clinical trials and approval status[edit]

A randomized study of rintatolimod (AMP 516 Phase III clinical trial for treatment of CFS) in the USA was completed as far back as 2004.[36] In early 2015 the AMP 511 open-label study of rintatolimod in CFS is still recruiting participants.[37] Open-label studies are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the benefits of the investigational drug until marketing approval is obtained.[38] Hemispherx management had missed several target deadlines for new drug application (NDA) filing in the past, including the end of 2005, the third quarter of 2006, and the first quarter of the year 2007.[39] In October 2007, the US Food and Drug Administration (FDA) Ampligen NDA was filed.[7][40] In December 2009 the FDA issued a CRL refusing Hemispherx's new drug application for rintatolimod's treatment of CFS. The FDA concluded that the two RCTs "did not provide credible evidence of efficacy." The agency recommended a minimum of one additional six month 300 patient study, and rodent carcinogenicity studies.

Studies including CFS studies are ongoing.[41] On January 12, 2015, the company announced Ampligen has been found to improve NK cell function in human CFS patients.[42]

Ampligen is taken intravenously. It is generally administered twice weekly for periods of one year or longer. Two toxicology studies are completed that establish the safety of intranasal and intramucosal methods of Ampligen administration,[43] and Hemispherx has been researching their patented oral versions using nucleic acid technology related to rintatolimod.[44][45]


Approximately 760 patients have received rintatolimod as part of clinical trials in the US, representing about 75,000 doses. Some chronic fatigue syndrome patients have reported a complete recovery, with others reporting clear and measurable improvements,[46] although of course success has not been universal. The drug's method of action would have no effect on CFS lacking a pathogenic component as, for instance, engendered by clinical depression in absence of host-pathogen interaction. In the meaningful subset of CFS sufferers who do recover or improve with Ampligen administration more common benefits include betterment of cognitive skills, greater oxygen uptake and an increase in energy, and a more positive outlook on life. These improvements can be measured on the Karnofsky scale.[47][48]

Side effects and safety[edit]

An independent review of Ampligen clinical trials in chronic fatigue syndrome was published in the December 2006 issue of the Journal of Clinical Virology.[49] It concluded that Ampligen has been "generally well tolerated", with a "low incidence of clinical toxicity", particularly when compared to the toxicity of the diseases it is used to treat. "No serious safety issues have resulted from the administration of ~75,000 doses IV (most commonly 400 mg) twice weekly for up to one year periods or greater. Animal toxicity studies support this observation in humans with primates demonstrating the greatest margin of safety."[50] A mild flushing reaction has occurred in about 15% of patients, and more rarely reported side effects include chills, fever, malaise, leukopenia, neutropenia and leukocytosis. Some of these side effects may be attributed to a temporary Herxheimer reaction in response to pathogen die off. According to Hemispherx and patient testimonials, side-effects when they occur usually subside within three to four months or less.[51][52]


Twice, in 1998 and 2000, Hemispherx received notices of violation from the FDA for promoting rintatolimod as safe and effective before FDA approval, in violation of the Federal Food, Drug, and Cosmetic Act.[53][54]

Also in the late 1900s, Manuel Asensio, a notorious short seller and former investment banker since expelled from the securities industry,[55][56] reported on Hemispherx, saying the company was overvalued. He criticized Hemispherx and its rintatolimod results,[57][dead link] alleging a variety of misdemeanors including accusations of refusing to supply rintatolimod after clinical trials have ended,[58][dead link] and issuing misleading results to widen markets for rintatolimod.[59][dead link]

In 1998, Hemispherx Biopharma filed a complaint against Asensio and his company, alleging defamation, conspiracy and interference with its business relations through a short-selling plot.[60] After a jury rejected the defamation claims against Asensio, a mistrial was declared.[61]

The following year, on November 2, 1999, Mary Schweitzer, a chronic fatigue syndrome patient who had been treated with rintatolimod, raised the question of why Ampligen has never been fast-tracked by the US public health authorities at the Chronic Fatigue Syndrome Co-ordinating Committee of the U.S. Department of Health and Human Services.[62] Grassroots activism for FDA approval of Ampligen grew and continues. Current efforts in 2015 to spur FDA approval of Ampligen include petitions,[63] appeal for congressional hearing,[64] and popular social media group organizing.[65][66][67][68]

Digital stock advisory The Street[69] journalist, Adam Feuerstein,[70] has published articles harshly critical of Hemispherx BioPharma, Inc., for over half a decade. In June 2009, Mr. Feuerstein alleged the company was "seeking to divert investors' attention away from the delayed approval of Ampligen as a treatment for chronic fatigue syndrome" by issuing three press releases in seven days about research from 2007 into possible applications for Ampligen as a flu vaccine booster, in which Hemispherx stated that Ampligen could be used against the H1N1 swine flu.[71] The Street article also alleged the press releases were misleading because they implied the research had been done in 2009. When Hemispherx offered Ampligen as a potential H1N1 vaccine or vaccine booster the U.S. government turned them down and Mr. Feuerstein wrote, "Hemispherx Biopharma has been shut out of the U.S. government's efforts to stockpile vaccine against the H1N1 flu."[72] Mr. Feuerstein's subsequent articles on Hemispherx BioPharma for The Street continue to run in similar vein.

Other uses[edit]

Rintatolimod is designed to boost cellular defenses against viruses and tumors, and can be used for Avian Flu,[73][3][74] AIDS,[75][76] and other depressed immune-system related diseases. Studies using Ampligen are in progress and in preparation.[77] Other suggested uses include Ebola and Smallpox.[78] Extremely promising results of a new Ebola/Ampligen rodent study by the U.S. Army Medical Research Institute of Infectious Disease (USAMRIID) were published February 2, 2015.[79][80] Hemispherx and USAMRIID will jointly present these new findings in Washington, D.C., on March 25-28, 2015, at the "7th Annual International Symposium on Filoviruses – Ebola: West Africa and Recent Developments." The conference brings together experts from all over the world to deal with the various aspects of controlling Ebola outbreaks in West Africa and elsewhere.[81]

See also[edit]

  • ALFERON N Injection® [82]


  1. ^ Official website
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  31. ^ "Cellular antiviral pathways of innate immunity are not subject to the mutational pressures of rapidly dividing viruses, which suggests that - even in the face of viral mutation – biological modifiers activating innate immunity are likely to continue to show sustained biological activity." USAMRIID Ampligen(R)/Ebola Rodent Study (2015)
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  82. ^ "ALFERON N Injection®"

External links[edit]